Local anaesthetics are drugs that provoke a reduction in sensibility and/or motor functions, in the area of application to the body, by the blocking of nerve conduction. Ideally, a local anaesthetic should neither provoke irritation nor damage to nerve tissue or other tissues close to the area of application. Complementarily, it is desirable that its action remains limited to the area of application, so as to avoid anesthetising other areas and undesirable systemic effects. Furthermore, it is desirable that the analgesic action is prolonged in order to confer an activity exceeding the duration of the pain stimulus (e.g. the time of the surgical intervention).
With the intent of increasing the power and time of activity, as well as reducing the potential adverse effects, various approaches have been attempted to produce local anaesthetics. These include: the combined use of vasoconstrictor agents (e.g. epinephrine), the development of anaesthetic molecules having increased affinity for nerve tissues (e.g. bupivacaine, ropivacaine), the use of formulations in the form of liposomes (e.g. liposomal lidocaine—Elamax®). However, these approaches have the disadvantages of local collateral effects (e.g. tissue necrosis due to prolonged vasoconstriction) or systemic collateral effects (e.g. the risk of cardiac arrhythmia and other cardiovascular problems).
Another approach that has been used is the production of formulations of prolonged-release micro-particles with sizes of over 1 micrometer, based on the use of biodegradable polymers, such as those presented in the publications WO 95/09613, WO 97/49391, EP 1 132 080, WO 02/58670, WO 06/013309, WO 06/047279 and in a series of scientific articles.
However, the large majority of these local anaesthetic formulations have the disadvantage of requiring injection in order to achieve optimal efficiency.
It is worth pointing out that, in the case of injectable formulations, apart from the need to use sterile formulations and administration devices, the process of injecting anaesthetics is painful and causes discomfort, especially in the case of children or in patients with an aversion to injections.
In this context, the topical application of anaesthetics to the skin is an interesting alternative for administering local anaesthetics. However, their application is limited by the low permeability of the skin and by the limited activity time of these formulations.
The low permeability of the skin is due, amongst other factors, to the barrier created by the corneal layer which is formed of corneocytes, having a lipid bilayer that increases resistance to ionised or low liposoluble substances. Thus, the flow through the skin depends on the chemical characteristics of the substances. As a rule, lipid drugs are absorbed through the cornea layer, with variable permeation coefficients, and hydrophilic drugs are almost exclusively absorbed by the paracellular route, with almost constant permeation coefficients. Due to the difficulty of controlling skin penetration by the drugs, chemical and physical agents, as well as carrier systems are presently being studied to overcome such shortcomings. With reference anaesthetic products for topical use on the skin, such as, for example, EMLA® cream (a cream containing 2.5% lidocaine and 2.5% prilocaine, by AstraZeneca do Brasil Ltda.), quite apart from offering inferior anaesthetic efficiency compared to injectable anaesthetics, require times of 1 to 2 hours to produce satisfactory anaesthesia on healthy skin, depending on the type of procedure, with the time of initial activity varying according to the distinct areas of the body (skin or mucosa) and the different skin conditions (with lesions, healthy or thick).
Therefore, the products used as local anaesthetics known and marketed in the actual state-of-the-art present inconveniences. In the case of injectable products, these are related to the manner of administration since the injection process is painful and causes discomfort. On the other hand, in the case of products for topical application to the skin, the disadvantages are related to the low absorption through the skin, length of time to take action and inferior anaesthetic efficiency.
Therefore, intending to obtain local anaesthetic products with appropriate safety and efficiency profiles, administration not requiring injection and reduced time of initial activity, the present invention is the result of research concerning the efficiency of anaesthetic formulations in which the local anaesthetic agent is contained in polymeric nanoparticles, when these are applied topically.
Despite the existence of accounts relating the production of anaesthetic agent nanoparticles in the scientific literature (e.g. Gorner T. e col. “Lidocaine-loaded biodegradable nanospheres I. Optimization of the drug incorporation into the polymer matrix”. Journal of Controlled Release 57 (1999) 259-268; Polakovic M. e col. “Lidocaine loaded biodegradable nanospheres II. Modelling of drug release”. Journal of Controlled Release 60 (1999) 169-177; Chung, T. e col. “Effects of solvent evaporation rate on the properties of protein-loaded PLLA and PDLLA microspheres fabricated by emulsion-solvent evaporation process”. J Microencapsul. 19 (2002) 463-71); Schwarz C & Mehnert W; “Freeze-drying of drug-free and drug-loaded solid lipid nanoparticles (SLN)”. INT. J. PHARM (1997), V157, P171-9.; Govender T e col.; “Defining the drug incorporation properties of PLA-PEG nanoparticles”. INT. J. PHARM (2000), V199, p95-110; and in patent documents (e.g. WO 06/056064 that describes a nanoparticulate formulation for injectable administration, mainly intravenously), to the best knowledge of the present inventors, there does not exist any reference in the actual state-of-the-art relating to the efficiency of a local anaesthetic product for topical application to the skin or mucosa comprising an anaesthetic agent in polymeric nanoparticles or any reference to the fact that such a formulation may present superior efficiency to non-nanoparticulate anaesthetic formulations for topical use. In the same context, there is no reference to the surprising fact confirmed by the present inventors that the formulation of anaesthetic agents in polymeric nanoparticles may lead to increased anaesthesia time and better definition of the anaesthetic effect compared to non-nanoparticulate formulations.
In this context, it should be stressed that U.S. Pat. No. 6,203,802 describes methods for the treatment of the superficial layers of the epidermis based on topical application, to the skin, of polymeric nanoparticles encapsulating at least one active ingredient but, however, does not make any reference whatsoever to polymeric nanoparticles for carrying local anaesthetic agents nor any reference whatsoever to the use of such a formulation to cause local anaesthesia, with activity occurring in the derm.